The main obstacle to RNA-interference-based inhibitors is delivering them into primary cells that are highly recalcitrant to nucleic acid uptake. As a result suppression of target gene expression within these cells for both biological and therapeutic purposes has been a major issue. In recent years there have been several advances in siRNA-carrier design that have enabled efficient and cell-specific siRNA delivery. However, formulation of these carriers is extremely cumbersome and cost-prohibitive for preliminary laboratory testing. We propose to develop novel, cost-effective, easy-to-formulate and non-immunogenic siRNA carriers for the cell-specific delivery of siRNA in vivo. These carriers will be formulated from two components- (1) a non-immunogenic protein/peptide component that binds the immunoglobulin Fc-region with a high affinity coupled to a siRNA binding domain and (ii) an antibody component capable of recognizing a specific cell-surface receptor and inducing internalization. Simple mixing or incubation of the carrier with the antibody will yield a reagent capable of siRNA delivery to the desired cell type. Importantly, delivery to the target cell type/organ will be achieved through simple intravenous injections. We will generate siRNA carriers to each of the human immune cell subtypes and defined organs/tissues and evaluate siRNA treatment efficacy in relevant murine models of human disease. The successful completion of our research plan is expected to lead to the establishment of easily translatable delivery platforms for the preclinical evaluation of potential siRNA therapeutic candidates.